Hindawi Publishing Corporation Disease Markers Volume 2015, Article ID 419124, 6 pages http://dx.doi.org/10.1155/2015/419124
Research Article The Value of Circulating Nogo-B for Evaluating Hepatic Functional Reserve in Patients with Cirrhosis Maoyao Wen,1 Ruoting Men,1 Zongze Yang,2 Xuelian Dan,1 Wenchao Wu,3 Xiaojing Liu,3 and Li Yang1 1
Division of Digestive Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China Creation and Management of a Tumour Bank, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China 3 Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China 2
Correspondence should be addressed to Xiaojing Liu;
[email protected] and Li Yang;
[email protected] Received 21 December 2014; Accepted 1 April 2015 Academic Editor: George Perry Copyright © 2015 Maoyao Wen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To examine Nogo-B in liver tissues and plasma of patients with liver cirrhosis and associate them with various clinical parameters. Materials and Methods. Nogo-B protein expression was examined by immunohistochemistry in 24 human fibrotic/cirrhotic liver specimens and 10 healthy controls. We determined plasma Nogo-B levels by enzyme-linked immunosorbent assay in 301 patients with liver cirrhosis and 153 healthy controls, and then analyzed various clinical parameters. Results. Nogo-B was mainly expressed in nonparenchymal cells in the liver and was marked increased in liver with significant fibrosis/cirrhosis compared to controls. Moreover, Metavir F4 showed a higher level of expression than F2. Plasma Nogo-B levels were significantly higher in cirrhotic patients than in healthy controls and were the highest in Child-Pugh class C patients. Plasma Nogo-B levels were positively correlated with Child-Pugh scores. However, there was no relationship between plasma Nogo-B levels and etiology of liver diseases, ALT, AST, platelet counts, and the severity of esophagogastric varices. Conclusions. Nogo-B is mainly expressed in hepatic nonparenchymal cells and is present in plasma. Abnormally high plasma levels of Nogo-B are associated with hepatic cirrhosis and Child-Pugh score, but not correlated with the grade of liver inflammation or portal hypertension. Plasma Nogo-B may be a novel surrogate marker to reflect liver function reserve.
1. Introduction Liver fibrosis/cirrhosis is a major cause of mortality around the world and the development of cirrhosis has been considered to be an irreversible event [1, 2]. Prognosis of patients with liver cirrhosis often depends on their hepatic functional reserve. Blood tests play pivotal roles in the clinical assessment of liver function reserve. Clinical classification systems, such as model for end-stage liver disease (MELD) and ChildPugh scoring systems, are widely used. Even radiographic examination of the remnant liver volumes can be helpful [3]. It is desirable to have a simple noninvasive blood test that reflects both the stage of liver fibrosis and functional reserve. Nogo-B is a member of the reticulum (Rtn) family of proteins localized primarily in the endoplasmic reticulum
(ER) and is widely distributed in cardiac myocyte, vascular endothelial cell, smooth muscle cell, testis, and other tissues [4–6]. Recent studies have shown that Nogo-B levels are significantly elevated in rat with cirrhosis, whereas low levels of Nogo-B suggest the absence of liver fibrosis [7]. In our previous study, we found that the plasma Nogo-B levels in patients with hepatic cirrhosis were significantly higher than healthy controls [8]. As a potential indicator of hepatic cirrhosis, the correlation between Nogo-B and clinical characteristics of cirrhosis remains unclear. Thus, we examined Nogo-B protein expression in fibrotic/cirrhotic liver tissues by immunohistochemistry and further investigated hepatic cirrhotic patients with different etiology and severity. Then we analyzed the relationship between plasma Nogo-B levels
2 and the commonly used clinical parameters of liver function in all patients.
2. Methods 2.1. Subjects. Fibrotic/cirrhotic liver specimens were obtained from 24 patients who underwent liver surgery for a variety of liver diseases. Twelve of the specimens showed Metavir stage 2 (F2) and the other 12 showed stage 4 (F4) fibrosis. The 10 healthy liver specimens were from patients who underwent liver surgery for benign focal lesions [9]. All the liver specimens were provided by the Department of Pathology, West China Hospital, Sichuan University. For plasma Nogo-B analysis, 301 patients of hepatic cirrhosis were enrolled in the Division of Digestive Diseases, West China Hospital, Sichuan University, from March 2012 to March 2014. 152 patients had hepatitis B cirrhosis, 83 were alcoholic cirrhosis, and 66 were primary biliary cirrhosis (PBC). The diagnosis of cirrhosis was made based on imaging studies and impaired liver synthetic function [10]. Patients with cardiovascular disease, kidney diseases, central nervous system disorder, chronic obstructive pulmonary diseases (COPD), and pulmonary artery hypertension which might affect plasma Nogo-B levels were excluded [11, 12]. The normal control group was composed of 153 healthy volunteers. All subjects provided written informed consents. This study was approved by the medical ethics committee of the West China Hospital, Sichuan University. 2.2. Collection of Samples and Clinical Parameters. Blood samples from patients and healthy controls were obtained. The plasma was immediately separated by centrifugation at 800 g for 10 minutes at room temperature and stored at −80∘ C. Parameters of liver function, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelet (PLT), were collected from the Department of Clinical Laboratory, West China Hospital, Sichuan University. The volume of ascites was observed by ultrasound. Patient’s Child-Pugh class/score were calculated. Esophageal and gastric varices were screened by esophagogastroduodenoscopy. The varices were defined as either large (>5 mm) or small (
